P-022: THERAPEUTIC EFFECTS OF GBT1118 ON SKELETAL MUSCLE ENERGETICS AND FUNCTION IN SICKLE CELL MICE
Authors: MICHEL C., MESSONNIER L., GIANNESINI B., VILMEN C., BENDAHAN D.
Journal: HemaSphere (2022)

Purpose: Sickle cell disease (SCD) is an hemoglobinopathy ultimately resulting red blood cells sickling. SCD patients suffer from anemia, arterial oxyhemoglobin desaturation, hematologic and hemodynamic abnormalities, all of which disrupt oxygen supply and can reduce exercise capacity and quality of life. Strenuous exercise in SCD patients may induce hemolysis, an early lactate accumulation, an intracellular acidosis, all of which are potential triggering factors for sickling and vaso-occlusive crises. GBT1118 is a HbS polymerization inhibitor which can increase hemoglobin affinity for oxygen and the corresponding supply to tissues. On that basis, we hypothesized that GBT1118 could dampen skeletal muscle energetics and function. Materials and methods: Skeletal muscle energetics and function of sixteen Townes mice (2 ± 0.5 month-old) were assessed in response to a standardized Rest-Stimulation(1Hz)-Recovery protocol before and after an 8-week period (8WP). Investigations were conducted using a setup designed to be operational inside a 7T horizontal MRI scanner (PharmaScan-Bruker). The setup allows (i) magnetic resonance imaging, (ii) muscle force measurements and (iii) 31P-magnetic resonance spectroscopy. Assessments conducted before and after the 8WP were identified with number 1 (SCDGBT1) and two (SCDGBT2). Ten mice received a chronic supplementation of GBT1118 (4g/kg in chow) during the 8WP (SCDGBT), whereas six mice had access to not supplemented chow (SCDCON). Results: The specific peak force (sPf) measured at the beginning of stimulation significantly increased over the 8WP (SCDCON2 +68%, p < 0.05). This increased initial sPf was also present in SCDGBT2 as compared to SCDGBT1 (+ 30%, p < 0.05). Over the entire stimulation session, the overall specific [TM1] force production (sTFP) significantly increased over the 8WP (SCDCON2 +32%, p < 0.05, Figure 1). The increased sTFP was also present in SCDGBT2 as compared to SCDGBT1 (+ 25 %, p < 0.05). However, the sTFP-normalized pHi reduction and sTFP-normalized phosphocreatine (PCr) breakdown significantly decreased in SCDGBT2 as compared to SCDGBT1 (p < 0.05, Table 1). Conclusion: In the control condition, the 8-week period was accompanied by a significant increase in specific total force production. Such an increase has been previously reported from 3 to 10 weeks of age (+ 33%). Overall, the increased specific total force production we reported was related to time and cannot be accounted for by GBT supplementation. In SCDGBT, the expected increased force production related to time was associated to a reduced acidosis and PCr breakdown which were not found in the control condition. For a given amount of force, SCDGBT mice muscle would experience a lower net proton accumulation and a reduced net PCr consumption. This reduction of both acidosis and PCr consumption could illustrate a diminished cost of contraction in response to GBT1118 supplementation which could be related to an improved contractile efficiency as previously described in humans. SCD mice treated with GBT1118 exhibit a reduced acidosis for a given force. Given that acidosis is a potential triggering factor of sickling, GBT would protect SCD muscle against the consequences of sickling. One could speculate that SCD patients receiving GBT1118 might be able to perform exercise with a reduced exposure to sickling.Specific total force production in SCDCON and SCDGBT before and after the 8-week period. Each point represents a single measurement and lines are linking consecutive points. p-values are mentioned on the top of the figure.Metabolic indices in SCDCON and SCDGBT before and after the 8-week period. The authors do not declare any conflict of interest